Our long-term objective is to understand the neural mechanisms that enable currently relevant information to optimally influence cognition and behavior. As the next step in achieving this objective, the goal of this proposed project is to test the hypothesis that the neural system for working memory (WM) is information-domain-dependent and hierarchically organized. We propose that items, such as objects, words, and locations, are represented at the lower levels of this hierarchy while information about relationships among these objects and with potential responses and rewards is represented at higher levels of this hierarchy in more anterior regions of the prefrontal cortex using similar neural mechanisms for both types of information. We will test this hypothesis using functional and anatomical magnetic resonance imaging in healthy young adults, and individuals with multiple sclerosis. We will measure the effects of memory load, repetition, and updating on the fMRI activation magnitude and pattern, directly comparing these effects for item vs. relational information. fMRI functional connectivity during WM for items will be contrasted to functional connectivity during WM for relations to ascertain whether interactions among prefrontal areas and between prefrontal areas and sensory areas are different for these different information types. The necessity of these interactions will be tested by using DTI tractography in individuals with multiple sclerosis to test whether WM performance for items depends on the integrity of different white matter tracts than does WM for relational information. The study aims to test whether a conceptual link can be identified between working memory maintenance of items, such as objects, locations, and words, which has been extensively studied, and executive control functions, which are much less well understood. This goal is highly relevant to the mission of the agency because these higher cognitive functions are disrupted in many mental disorders and neurological diseases. Without a clear understanding of the neural systems that make these abilities possible, we have little to offer for treatment or prevention of cognitive dysfunction.